This Project should be perceived as a completely new project. It is built on the premise that standard cytotoxic[unreadable] therapy has been unsuccessful in the advancement of treatment for patients with soft tissue sarcoma (STS)[unreadable] and that the future depends on the identification of new targeted agents. Using a laboratory based approach[unreadable] of drug discovery with target validation, we believe we have made considerable progress toward this end.[unreadable] The drugs we have thus far identified include flavopiridol, the cyclin dependent kinase inhibitor, sorafenib[unreadable] (BAY-43 9006), an inhibitor of Raf-kinase B, 17-AAG, the inhibitor of HSP90, and Nutlin, the Roche[unreadable] compound that inhibits MDM2. Even though each of these agents inhibits a different target, we have[unreadable] observed that there is a generalized effect of cell cycle arrest. In view of this, the Project has been renamed[unreadable] "Laboratory and Clinical Development of Cell Cycle Active Agents in the Treatment of Soft Tissue Sarcomas"[unreadable] to reflect a common underlying effect of cell cycle modulation by these new targeted agents. We believe this[unreadable] approach in drug development greatly expands our strategy to identify new agents in the treatment of soft[unreadable] tissue sarcomas. It also clearly extends our therapeutic spectrum beyond flavopiridol to other agents[unreadable] currently in clinical development. The laboratory studies outlined have provided the foundation for three[unreadable] clinical trials with the inclusion of defined correlative studies in the treatment of STS. The specific aims of[unreadable] this project are: 1. To conduct the phase I clinical trial of doxorubicin and flavopiridol in STS with assessment[unreadable] of correlative markers of response. 2. To conduct a multi-center phase II clinical trial of sorafenib in patients[unreadable] with STS. 3. To conduct a multi-center phase II clinical trial of 17-AAG in patients with STS. 4. To identify[unreadable] and validate in the laboratory new targets for the treatment of STS, including CDK4/CDK2, Raf-kinase B,[unreadable] HSP90, MDM2 and E2F1. We believe this approach will lead to the development of new therapeutic[unreadable] approaches that will have a profound impact on the successful treatment of patients with this rare but often[unreadable] fatal disease.